Issue:October 2013

BIOAVAILABILITY ENHANCEMENT - Navigating a Broad Spectrum of Solubilization Technologies: Part II of III

In September’s issue, The Second Quadrant focused on technology options available and in use today to address bioavailability challenges of poorly soluble drugs. In particular, when technologies are best suited for APIs based on compound characteristics and the target product profile. In Part II of this series, experts from nine companies discuss key challenges faced that are related to these technologies, and combinations or techniques that can improve solubilization results. This part concludes with thoughts on untapped opportunities that may be exploited with a better understanding of the various options available and their respective applications.

As in Part I, the broad set of solubilization technologies companies represented include those offering lipid-based solubilization, amorphous solid dispersions, particle size reduction, particle engineering, nanoparticles, and co-crystallization.


Q: What do you view as the primary challenges faced today in formulation to achieve enhanced bioavailability that directly correlate with solubilization technologies?

Dan Dobry: A particularly challenging area is the oral delivery of BCS class IV compounds that have low permeability and low solubility. These compound properties are driven by requirements to hit complex therapeutic targets. Some of these compounds have a higher molecular weight than that commonly thought to be in “druggable” space. These compounds are particularly difficult to formulate and require the addition of multiple technologies to successfully deliver the required payload – such as those mentioned previously. Formulating each compound requires committed diligence and a partnership with the client. Fortunately for clients, the Bend Research experience with over 1,000 compounds means that we’ve come across many of the common issues with formulation. Sometimes we’ve engaged on existing formulations that had acceptable performance to support a Phase I program, but that are unacceptable for Phase II, Phase III, or commercial application. Using fundamental science and engineering principles and our 20+ years of experience in dealing with low-solubility compounds, we’ve identified a broad array of dispersion formulation approaches as well as complementary technologies, such as nanoparticles and nanocrystals. This means that many of these compounds can be solubilized using the appropriate approach based on the key factors of performance, stability, manufacturability, and the target product profile for the patient.

Tom Dürig: The primary challenge is to translate increased solubility in gastrointestinal fluid into increased absorption and bioavailability. Recent work by Dahan et al has highlighted the importance of understanding the mechanism of different solubilization approaches and their effect on intestinal membrane permeability.1,2 It has been shown that cyclodextrin-, co-solvent-, and surfactant-based systems resulted in high solubility, but decrease transmembrane flux as compared with amorphous solid dispersions. A thorough understanding of in vivoeffects of excipients and delivery systems in addition to their solubilization effects is therefore key.1,2

Dr. Joan Feixas: Although the number of published bioavailability studies is limited, it is clear that co-crystals can significantly increase the bioavailability of poorly soluble APIs (BCS class II and IV drugs). In general, there is a correlation between the improvements of bioavailability and the improvement of API solubility induced by the co-crystal. However, it is very difficult to predict the solubility enhancement of the co-crystal from the physical chemical properties of the co-former. In 2011, draft guidance for industry on regulatory classification of pharmaceutical co-crystals was released by the FDA. In this draft, and from the regulatory standpoint, co-crystals were not defined as a new chemical entity (like a salt) but, instead, as a drug product intermediate (dissociable “API-excipient” molecular complexes). This consideration opened a new path for generic companies to file ANDAs, avoiding the 505 (b)(2) regulatory track. In the last guidance issued in April 2013, the FDA confirms this view and even allows fine chemical manufacturers to produce pharmaceutical co-crystals (a drug product intermediate) in a cGMP API chemical plant.

Dr. Filipe Gaspar: There is still a lot to do before being able to correlate technology with improved bioavailability. Understanding dissolution kinetics, supersaturation, and crystallization processes, free drug concentrations, and food effects, among others, is not trivial but will surely help in the adoption of solubilization techniques.

Dr. Robert Hoerr: Primary challenges are solubility and permeation. The particle reduction technologies have the potential to improve solubility and dissolution. To date, the commercialization for nanoformulation technologies has been somewhat limited due to batch processing, cost, and multi-step processes. The requirement to maintain a narrow particle size distribution as the process is scaled has been difficult. Another challenge has been making solid solutions. ENS transforms the solvent solution of API and excipients directly into a drug-excipient solid solution with a very narrow targeted particle size distribution. ENS-produced powders can improve both solubility and dissolution rate. ENS has a very high process yield and can be used to formulate small amounts of API to enable in vivo and in vitro testing at early phases of drug discovery and development.

Keith Hutchison: When an API is formulated using a lipid-based solubilization technology, the effect of digestion on the excipients can have a significant effect on the quantity of solubilized drug in the gut and the extent to which absorption is affected by the presence of food. In vitro digestion tests are therefore used by Capsugel DFS to ensure that the most robust lipid formulations are designed, tested, and proposed for customer projects. Testing protocols are based on the advancements achieved by the Lipid Formulation Classification System (LFCS) Consortium (, of which Capsugel is a founding and active member. LFCS is playing a critical role in exploring the relationship between lipid digestion/dissolution and drug absorption and establishing standardized in vitro tests for lipid formulations, which is a key factor in expanding the market application of lipid-based technology.

Dr. Dave Miller: An important challenge facing the development of amorphous drug products is the prediction of physical stability. Recent advances to in silico modeling with the use of solubility parameters and the application of Flory-Huggins theory are helping to provide better understanding of drug-polymer miscibility, which directly correlates to physical stability. These tools are also helping to focus formulations screening efforts on the most viable carriers and drug-to-polymer ratio ranges, ultimately leading to more rapid development of amorphous formulations that are physically stable for pharmaceutically relevant time periods. Continued development of these in silico modeling tools will provide fundamental understanding of the mechanisms behind amorphous stability allowing for the development of amorphous products with well-understood and defined stability profiles. This fundamental understanding will help ease anxieties regarding the metastable nature of amorphous drug products and thereby lead to more widespread adoption of amorphous formulation technologies.

Dr. Deepak Tiwari:
One of the most difficult delivery challenges involves oral delivery of BCS class IV molecules. In this area, we have seen that the use of combinations of delivery technologies may be of benefit.


Q: Are there unique or emerging combinations of technologies that expand the benefits of each, and can improve the bioavailability of a compound?

Dan Dobry: Depending on the compound properties and delivery profile desired (including regional permeation differences), there are multiple technology options available. For example, combining a spray-dried dispersion solubilization technology with a modified-release osmotic delivery system, such as a swellable core system (also known as “push/pull”), can provide solubilized active at different regions of the GI tract. Another example is to combine excipients that prolong a “supersaturated” state in the small intestine. This has proven to be particularly successful for compounds that have good solubility at gastric pH, but poor solubility at intestinal pH. A final example is a process improvement that expands the usefulness of common methods of solubilization. Some compounds that have very low solubility, even in common organic solvents, can be successfully spray dried into amorphous dispersions at commercial throughputs by rapidly heating a suspension of active just before spray-drying.

Tom Dürig: Hot-melt extrusion with supercritical CO2 injection is a particularly interesting combination of technologies in which our scientists are working. Hot- melt extrusion has obvious advantages; it can be solvent free, potentially continuous and easily scaleable with a relatively small manufacturing foot print. However, there are well-known shortcomings vis-à-vis spray-drying, such as lower mixing efficiency and a narrower processing window compared with dissolution in solvent and spray-drying. Supercritical CO2 acts as a solvent in the hot-melt extrusion process, thus enhancing drug-polymer mixing and increasing the processability window, due to its ability to act as a plasticizer and solvent. Lastly, the evaporation of CO2 during the process creates a porous extrudate microstructure, which aids in tablet compaction and dissolution. Another interesting opportunity is the combination of controlled-release technology with solubilization. Recent work has shown that it is possible to achieve extended drug release as well as continuous supersaturation with minimal precipitation for a period exceeding 10 hours.

Dr. Joan Feixas: It is well known that the solubility behavior of poorly soluble drugs can be improved significantly when a co-crystal form of the drug is used. However, the pharmaceutical co-crystallization can be combined with other technologies to further improve solubility and, therefore, bioavailability. For example, combining co-crystallization with supercritical fluid technologies, it is possible to obtain nanococrystals with an extended control of the particle morphology and the size distribution. These are key aspects for inhaled drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD).

Dr. Filipe Gaspar: Clearly there are and we expect to see in the near future a number of novel and combined technologies able to improve bioavailability and other quality attributes. At Hovione, we have for example fluidized spray-drying that provides the same benefits of spray-drying (for example in improving bioavailability) with a fluid bed drying and agglomeration process that results in powders with very unique properties. This is a technology that is broadly applied in other industries but still in its infancy for the production of drug products. Other examples of combined technologies include injection molding, supercritical CO2-assisted extrusion, spray-freeze-drying, and spray-drying of polymeric micelles or nanoparticles. Among emerging solubilization technologies, which may or may not prove to be viable in the marketplace, are spray-congealing, microfluidization, electrospinning, and emulsification.

Dr. Robert Hoerr: Recent advances in nanotechnology have enabled nanosized or nanostructured pharmaceutical particle engineering to provide enhanced efficacy, solubility, or bioavailability, thereby possibly lowering dose requirements. ElectroNanospray (ENS) is an alternative to solvent spray-drying without temperature or pressure limitations and with no additional processing steps. With ENS, excipients used for dry granulation and capsule coating can be repurposed to create nanoparticles with improved solubility, stability, and bioavailability. In addition, ENS’ highly controlled deposition capability lends itself to production of thin-layered structures that allow for unique drug/drug, drug/excipient, or drug/biologic combinations.

Keith Hutchison: When an API is solubilized in liquid or semi-solid lipids, the formula is filled into a capsule as a monolithic form. However, there are technologies available to solubilize a drug in high melting point waxy materials. Capsugel DFS is using its new solid lipid pellet technology to immobilize APIs in high melting point pharma excipients and produce spherical particles that are filled into capsules as powders. Additionally, polymers and polymeric capsules, eg, our Vcaps®Plus HPMC capsules, have been shown to reduce the risk of API precipitation in the small intestine to increase bioavailability – we therefore use these capsules in combination with lipid formulations when a risk of drug precipitation has been identified in vitro.

Dr. Dave Miller: KinetiSol is a novel processing technology that expands the space of compounds and excipients that are viable for amorphous formulation concepts. KinetiSol offers all the benefits of non-solvent processing that are provided by melt extrusion, yet offers distinct advantages over melt extrusion for particular applications. Specifically, KinetiSol reduces thermal stress on processed materials enabling fusion processing of thermally labile APIs and excipients. Also, according to the processes’ intense mixing mechanism, compounds are able to be rapidly solubilized in a molten polymer, well below the API’s melting temperature. This is particularly beneficial for high melting point compounds in which achieving target amorphous drug loadings in specific concentration-enhancing polymers can be particularly challenging by melt extrusion. Finally, by its unique mixing mechanism, KinetiSol is able to process highly viscous polymers without plasticizers or processing aids that would be needed for melt extrusion processing and that can negatively impact physical stability. The physical stability advantage is obvious, but this capability of KinetiSol also creates exciting new possibilities for novel amorphous dispersion compositions with unique dissolution and PK profiles. Ultimately, KinetiSol is providing a novel processing solution by which amorphous dispersion technology can be applied to insoluble compounds toward the end of improving bioavailability and enabling new, or improving existing, drug therapies.

Dr. Deepak Tiwari: Absolutely. We have been combining a number of approaches with good success. Unfortunately, we cannot go into specific details in a public forum, but the technologies we are using are complementary and not mutually exclusive.



Q: What are some of the gray areas in which your technology may be able to help overcome insolubility but where assumptions or lack of familiarity with the approach diminishes the exploration of a specific technology?

Dan Dobry: Many underestimate the need to customize the solution to the challenges and properties of each molecule or class of problem statements. We’ve encountered several scenarios in which the simple conversion of the API to the amorphous form or dissolution into a simple lipid carrier did not provide sufficient bioavailability enhancement. We have been able to “fix” or “optimize” many failed or substandard formulations through use of science-based approaches to solving the specific challenge a molecule presents. For example, a fast crystallizer often requires a much different approach than a highly lipophilic or “greasy” compound.

Tom Dürig: Many companies still lack familiarity with the techniques to produce amorphous dispersions beyond bench scale. There is an unnecessary mindset of avoiding spray-drying, which is one of the most powerful techniques. This avoidance tends to be due to assumptions that the environmental complications and costs associated with commercial-scale organic solvent use are prohibitive. Frequently, therefore, companies wish to explore only hot-melt extrusion. Additionally, as a result of the relatively small number of marketed amorphous dispersion products, many companies continue to shy away from solid dispersions, based on the assumption that it is, as yet, a risky and relatively unproven technology, which is not really the case when considering the spate of recent NDA approvals and the considerable pipeline under development.

Dr. Joan Feixas: Although the use of co-crystal technology with non ionisable or poorly ionisable APIs is well known, less familiar is the preparation of a co-crystal of a salt to form an ionic co-crystal consisting of a multicomponent solid with both neutral molecule and an electrically neutral ion combination. With this kind of co-crystal, it is possible to modulate the chemical physical properties of a drug salt. For example, co-crystals of fluoxetine·HCl (Prozac®) with different acidic coformers have been described and exhibited significantly different solubilities and dissolution rates. Recently, ionic co-crystals of inorganic salts with interesting properties have been also described.

Dr. Filipe Gaspar: For solid dispersion platforms in which spray-drying and hot-melt extrusion are the leading technologies, we still see some apprehension from some formulators to move with an amorphous form approach. This happens despite the significant advances in the underlining science and the growing number of solid dispersions reaching the market. We have come a long way in the past 8 to 10 years, but there is still a lot to do to reassure all of the value of this platform. For hot-melt extrusion, the quantity of material required for process development limits its use at early stages. Then there is reluctance to switch to the technology to mitigate clinical risk. Polymer degradation in hot-melt extrusion also needs further understanding and poses concerns during formulation development.

Dr. Robert Hoerr: Nanotechnology has significant promise, but the scalability of nanoformulation has proven difficult. One erroneous assumption is that electrospray cannot scale up beyond micrograms per minute. People are unaware of the progress that is being made toward preclinical scale manufacturing and reducing the cost of the equipment. We have developed a scalable modular component pathway to high-volume ENS production in the kilogram or larger per day range.


Keith Hutchison: Solubilization of drugs in lipid-based formulas is widely explored, but a general lack of familiarity with excipients, as well as with a systematic set of techniques for identifying the optimum formula can impede effective uptake of the technology, particularly for multicomponent systems of API in oil/surfactant/co-surfactant compositions. Many lower Log P APIs, eg, < 5, are often viable candidates for lipid formulations but are typically progressed with other enabling solubility-enhancement approaches.

Dr. Dave Miller: The KinetiSol process can be applied to create advanced amorphous dispersion systems for most poorly water-soluble compounds; however, where it adds most value is in the “gray area” space that contains compounds with high melting points, thermal sensitivity, poor organic solubility, or for compositions requiring polymers that are not amenable to fusion processing. Misconceptions regarding scalability or limited manufacturing experience with KinetiSol have likely been a deterrent for some to explore the technology. The reality is that prior to its adaptation to pharmaceutical manufacturing, the technology underlying KinetiSol was utilized extensively in the plastics processing industry to generate commercial products at a rate of several tons per hour. In the development of KinetiSol for pharmaceutical applications, the technology actually had to be scaled down to accommodate early development where API quantities are limited. So, the development of KinetiSol was quite different from most new technologies in that scaling went in the opposite direction. Therefore, the principles of scaling the KinetiSol process are well understood and easily applied. Although scaling is straightforward, for most products, scale-up is not required. KinetiSol processing at a development scale occurs within a batch size range of 50 to 300 g. Hence, formulation and process development are conducted in batch mode at a 50 g scale first, then the batch size is increased to around 250 g within the same compounder without influencing product properties. The process is then converted from batch to semi-continuous mode producing 250 g approximately every 30 seconds. Hence, production rates of about 30 kg/hr can be achieved within the same KinetiSol unit that is utilized to develop the formulation and process. For high-volume products, multiple KinetiSol units can be operated in parallel to meet throughput requirements.

Peter Nelson: In addition to the “urban myth” relative to amorphous content mentioned previously, micronization suffers from being an “unsophisticated” technology. It is simply not as “sexy” as some alternative solubilization technologies available today. Micronization, however, is an extremely versatile, scaleable, and time-tested process that can enhance the performance of solubility-challenged compounds. Like any process, micronization does have potential drawbacks, such as the potential for particle agglomeration, reduced flow characteristics, etc. If understood and proactively evaluated, however, these potential problems can be addressed. During early development of the compound, it is important to consider formulation and/or process strategies that can help mitigate the potential problems associated with our technology.

Dr. Deepak Tiwari: Again, because we use a number of technologies, there are a number of answers to this. In general, however, one needs to focus on bioavailability and not specifically on solubility. Bioavailability is driven by a number of factors. Keeping that in mind and combining approaches in a methodical development program is the quickest path to success.


In Part III of this series, solubilization technology experts will provide insights into recent breakthroughs in solubilization technologies, and what we can expect to see in the future. To ensure The Second Quadrant serves as a forum for interactivity and collaboration, I invite you to send your reactions, thoughts, and suggestions so we can continue our dialogue. I look forward to hearing from you.


1. Dahan A, Beig A, Ioffe-Dahan V et al. The twofold advantage of the amorphous form as an oral drug delivery practice for lipophilic compounds: increased apparent solubility and drug flux through the intestinal membrane. AAPS J. 2013, 15:347-353.
2. Dahan A, Miller J. Drug-precipitation permeation interplay: supersaturation in an absorptive environment. Eur J Pharmaceut Biopharmaceut. 2012,83:424-428.